WO2000002871A1 - Nouveaux inhibiteurs de l'angiogenese - Google Patents

Nouveaux inhibiteurs de l'angiogenese Download PDF

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Publication number
WO2000002871A1
WO2000002871A1 PCT/US1999/015200 US9915200W WO0002871A1 WO 2000002871 A1 WO2000002871 A1 WO 2000002871A1 US 9915200 W US9915200 W US 9915200W WO 0002871 A1 WO0002871 A1 WO 0002871A1
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WIPO (PCT)
Prior art keywords
phenyl
hydroxy
acetamidooxazole
valeramidooxazole
benzamidooxazole
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PCT/US1999/015200
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English (en)
Inventor
Mark E. Fraley
Randall W. Hungate
William F. Hoffman
William R. Huckle
Richard L. Kendall
Kenneth A. Thomas, Jr.
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority claimed from GBGB9822700.2A external-priority patent/GB9822700D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to CA002336848A priority Critical patent/CA2336848A1/fr
Priority to EP99937204A priority patent/EP1097147A4/fr
Priority to AU52082/99A priority patent/AU747427B2/en
Priority to JP2000559102A priority patent/JP2002520324A/ja
Publication of WO2000002871A1 publication Critical patent/WO2000002871A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to compounds which inhibit tyrosine kinase enzymes, compositions which contain tyrosine kinase inhibiting compounds and methods of using tyrosine kinase inhibitors to treat tyrosine kinase-dependent diseases/conditions such as neoangiogenesis, cancer, tumor growth, atherosclerosis, age related macular degeneration, diabetic retinopathy or inflammatory diseases, in mammals.
  • tyrosine kinase-dependent diseases/conditions such as neoangiogenesis, cancer, tumor growth, atherosclerosis, age related macular degeneration, diabetic retinopathy or inflammatory diseases, in mammals.
  • Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphosphate to tyrosine residues in protein substrates. Tyrosine kinases are believed, by way of substrate phosphorylation, to play critical roles in signal transduction for a number of cell functions. Though the exact mechanisms of signal transduction is still unclear, tyrosine kinases have been shown to be important contributing factors in cell proliferation, carcinogenesis and cell differentiation. Solid tumors which are treated by the present invention are cancers such as cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung.
  • cancers include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Additional examples include cancers in which overexpression or activation of Raf-activating oncogenes (e.g., K- ras, erb-B) is observed. More particularly, such cancers include pancreatic and breast carcinoma.
  • Raf-activating oncogenes e.g., K- ras, erb-B
  • tyrosine kinases are useful for the prevention and treatment of proliferative diseases dependent on these enzymes.
  • a method of treatment described herein relates to neoangiogenesis.
  • Neoangiogenesis occurs in conjunction with tumor growth and in certain diseases of the eye. It is characterized by excessive activity of vascular endothelial growth factor.
  • VEGF Vascular endothelial growth factor binds the high affinity membrane-spanning tyrosine kinase receptors KDR and Flt-1.
  • KDR mediates the mitogenic function of VEGF
  • Flt-1 appears to modulate non-mitogenic functions such as those associated with cellular adhesion. Inhibiting KDR thus modulates the level of mitogenic VEGF activity.
  • VEGF vascular growth in the retina leads to visual degeneration culminating in blindness.
  • VEGF accounts for most of the angiogenic activity produced in or near the retina in diabetic retinopathy.
  • Ocular VEGF mRNA and protein are elevated by conditions such as retinal vein occlusion in primates and decreased p ⁇ 2 levels in mice that lead to neovascularization.
  • VEGF receptor immunofusions inhibit ocular neovascularization in both primate and rodent models. Regardless of the cause of induction of VEGF in human diabetic retinopathy, inhibition of ocular VEGF is useful in treating the disease. Expression of VEGF is also significantly increased in hypoxic regions of animal and human tumors adjacent to areas of necrosis. VEGF is also upregulated by the expression of the oncogenes ras, raf, src and mutant p53 (all of which are relevant to targeting cancer). Monoclonal anti -VEGF antibodies inhibit the growth of human tumors in nude mice. Although these same tumor cells continue to express VEGF in culture, the antibodies do not diminish their mitotic rate.
  • VEGF tumor-derived VEGF does not function as an autocrine mitogenic factor. Therefore, VEGF contributes to tumor growth in vivo by promoting angiogenesis through its paracrine vascular endothelial cell chemotactic and mitogenic activities.
  • monoclonal antibodies also inhibit the growth of typically less well vascularized human colon cancers in athymic mice and decrease the number of tumors arising from inoculated cells.
  • VEGF-binding construct of Flk-1, Flt-1, the mouse KDR receptor homologue truncated to eliminate the cytoplasmic tyrosine kinase domains but retaining a membrane anchor, virtually abolishes the growth of a transplantable glioblastoma in mice presumably by the dominant negative mechanism of heterodimer formation with membrane spanning endothelial cell VEGF receptors.
  • Embryonic stem cells which normally grow as solid tumors in nude mice, do not produce detectable tumors if both VEGF alleles are knocked out. Taken together, these data indicate the role of VEGF in the growth of solid tumors.
  • KDR or Flt-1 are implicated in pathological neoangiogenesis, and these receptors are useful in the treatment of diseases in which neoangiogenesis is part of the overall pathology, e.g., inflammation, diabetic retinal vascularization, as well as various forms of cancer.
  • the compounds of the instant invention represent novel structures for the inhibition of KDR kinase.
  • a compound is disclosed in accordance with formula I :
  • X is O or S
  • R is H, Ci _ ⁇ o alkyl, C3-6 cycloalkyl, C5.10 aryl, halo, CF3, C3.10 heterocyclyl, or C5.10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R is H, C ⁇ _6 alkyl, C5.10 aryl, C5.10 heteroaryl, C3-6 cycloalkyl; said alkyl, aryl, heteroaryl or cycloalkyl optionally substituted with from one to three members selected from R ;
  • R is C ⁇ _6 alkyl, C5.10 aryl, C5.10 heteroaryl, C3-6 cycloalkyl; said alkyl, aryl, heteroaryl or cycloalkyl optionally substituted with from one to three members selected from R ;
  • R is H, C ⁇ _ ⁇ o alkyl, C3.6 cycloalkyl, C .Q alkoxy, C2-10 alkenyl, C2-10 alkynyl, C5.10 aryl, C3.10 heterocyclyl, C1-6 alkoxyNR R ⁇ , N0 2 , OH, -NH 2 or C5.10 heteroaryl, said alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R a is H, C ⁇ _ ⁇ o alkyl, halogen, CF 3) NO 2 , NHC(O)R*, OR, - NR NR7R8, R7R8, C5.10 aryl, C5.10 aralkyl, C 5 . 10 heteroaryl or C3.10 heterocyclyl, said aralkyl, aryl and heteroaryl optionally substituted with 1-2 groups of NO2, halo, C5.10 aryl, Ci-6 alkoxy, Cl-6 alkyl or CF3,
  • R* is H, or C ⁇ _ 6 alkyl, NHC(O)CHR(C 5 . 10 aralkyl), the aryl ring of the aralkyl being optionally substituted with 1-3 groups of OH, Cl-6 alkyl, or halo,
  • R is H, or C ⁇ _g alkyl
  • R7&R8 are independently H, C .IQ alkyl, C3-6 cycloalkyl, COR,
  • COOR, CO2, C5.10 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated rin containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
  • a pharmaceutical composition which is comprised of a compound represented by the formula I:
  • R , R , R and R are described as above or a pharmaceutically acceptable salt or hydrate or prodrug thereof in combination with a carrier.
  • Also included is a method of treating a tyrosine kinase dependent disease or condition in a mammal which comprises administering to a mammalian patient in need of such treatment a tyrosine kinase dependent disease or condition treating amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof. Also included is a method of treating cancer in a mammalian patient in need of such treatment which is comprised of admininstering to said patient an anti-cancer effective amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof.
  • Also included in the present invention is a method of treating diseases in which neoangiogenesis is implicated, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof in an amount which is effective for reducing neoangiogenesis. More particularly, a method of treating ocular disease in which neoangiogenesis occurs is included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt hydrate or pro-drug thereof in an amount which is effective for treating said ocular disease.
  • a method of treating retinal vascularization is included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof in an amount which is effective for treating retinal vascularization.
  • Diabetic retinopathy is an example of a disease in which neoangiogenesis or retinal vascularization is part of the overall disease etiology.
  • a method of treating age-related macular degeneration is also included.
  • alkyl refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cycloheptyl, cyclopentyl and cyclohexyl. When substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups of R a , described herein.
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present.
  • Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted with one to three groups of R a , when a substituted alkenyl group is provided.
  • alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon- carbon triple bonds may be present.
  • Preferred alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted with 1-3 groups of R a , when a substituted alkynyl group is provided.
  • Aryl refers to 5-10 membered aromatic rings e.g., phenyl, substituted phenyl and like groups as well bicyclic rings such as naphthyl.
  • Aryl thus contains at least one ring having at least 5 atoms, with up to two such rings being present, containing up to 10 atoms therein.
  • the preferred aryl groups are phenyl and naphthyl.
  • Aryl groups may likewise be substituted with 1-3 groups of R a as defined herein.
  • Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.
  • aralkyl is intended to mean an aryl or heteroaryl moiety, as defined herein, attached through a Cl-6 alkyl linker, where alkyl is defined above.
  • alkyl is defined above.
  • aralkyls include, but are not limited to, benzyl, naphthylmethyl, phenylpropyl, 2-pyridylmethyl, 2-imidazolylethyl, 2- quinolinylmethy, 2-imidazolylmethyl and the like.
  • heterocycle, heteroaryl or heterocyclic represents a stable 5- to 7- membered mono- or 7- to 10-membered bicyclic heterocyclic ring system, any ring of which may be saturated or unsaturated, aromatic or non-aromatic, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • Heterocycles include any bicyclic group in which any of the above-defined rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • the heterocycle, heteroaryl or heterocyclic may be substituted with 1-3 groups of R a .
  • Examples of such heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazoly
  • alkoxy refers to a substituent with an alkyl group of the designated length in either a straight or branched configuration, and may include a double or a triple bond, which is attached via an oxygen molecule.
  • alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, vinyloxy and the like.
  • halo or "halogen” is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.
  • Tyrosine kinase dependent diseases or conditions refers to hyperproliferative disorders which are initiated/maintained by aberrant expression of the activating ligands (e.g. VEGF) of the tyrosine kinases.
  • the activating ligands e.g. VEGF
  • Examples include psoriasis, cancer, immunoregulation (graft rejection), atherosclerosis, rheumatoid arthritis, angiogenesis (e.g. tumor growth, diabetic retinopathy), age related macular degeneration, etc.
  • X is O and all other variables are as originally described.
  • Still another aspect of the invention is realized when
  • R and R are C5.10 aryl or C5.10 heteroaryl
  • R is H, C ⁇ _ ⁇ o alkyl, C5.10 aryl, halo, CF3, or C5.10 heteroaryl; said alkyl, aryl, and heteroaryl being optionally substituted with from one to three members selected from R a ;
  • R is H, C ⁇ .g alkyl or C5.10 aryl, sai alkyl or aryl optionally substituted with one to three members selected from R ;
  • R & R are independently C .IQ alkyl, C5.10 aryl, or C5.10 heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted with from one to three members selected from R a ;and all other variables are as described above.
  • Schemes 1-3 for preparing the novel compounds of this invention are presented below.
  • the examples which follow the schemes illustrate the compounds that can be synthesized by these schemes.
  • the schemes are not limited by the compounds listed nor by any particular substituents employed for illustrative purposes.
  • the examples specifically illustrate the application of the following schemes to specific compounds.
  • Schemes 1 and 2 demonstrate to generalized protocols for the preparation of the required oxazoles from nitriles and diamides respectively.
  • Scheme 3 exemplifies the synthesis of a lactam substituted compound.
  • the reaction conditions employed are apparent from the specific examples that follow. Alternative conditions and protocols would be apparent to those skilled in the art.
  • amino thiazoles can be prepared as described in
  • the invention described herein includes a pharmaceutical composition which is comprised of a compound of formula I or a pharmaceutically acceptable salt, hydrate or prodrug thereof in combination with a carrier.
  • pharmaceutically acceptable salts and “hydrates” refer to those salts and hydrated forms of the compound which would be apparent to the pharmaceutical chemist, i.e., those which favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, absorption, distribution, metabolism and excretion.
  • Other factors, more practical in nature, which are also important in the selection are the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug.
  • a compound of formula I is present as a salt or hydrate which is non-pharmaceutically acceptable, this can be converted to a salt or hydrate form which is pharmaceutically acceptable in accordance with the present invention.
  • a counterion e.g., an alkali metal cation such as sodium or potassium.
  • suitable counterions include calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanol- hydroammonium, etc.
  • An appropriate number of counterions is associated with the molecule to maintain overall charge neutrality.
  • an appropriate number of negatively charged counterions is present to maintain overall charge neutrality.
  • Pharmaceutically acceptable salts also include acid addition salts.
  • the compound can be used in the form of salts derived from inorganic or organic acids or bases.
  • examples include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy- ethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention.
  • any variable e.g., aryl, heteroaryl, R , etc
  • its definition on each occcurence is independent of its definition at every other occurrence, unless otherwise stated.
  • the compounds of the invention can be formulated in a pharmaceutical composition by combining the compound with a pharmaceutically acceptable carrier. Examples of such compositions and carriers are set forth below.
  • the compounds may be employed in powder or crystalline form, in solution or in suspension. They may be administered orally, parenterally (intravenously or intramuscularly), topically, transdermally or by inhalation.
  • the carrier employed may be, for example, either a solid or liquid.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers include syrup, peanut oil, olive oil, water and the like.
  • the carrier for oral use may include time delay material well known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • Topical applications may be formulated in carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders.
  • Such topical formulations can be used to treat ocular diseases as well as inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis, delayed hypersensitivity reactions and the like.
  • oral solid dosage forms examples include tablets, capsules, troches, lozenges and the like. The size of the dosage form will vary widely, but preferably will be from about 25 mg to about 500mg.
  • oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like.
  • injectable dosage forms include sterile injectable liquids, e.g., solutions, emulsions and suspensions. Examples of injectable solids would include powders which are reconstituted, dissolved or suspended in a liquid prior to injection.
  • the carrier is typically comprised of sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections. Also, various buffering agents, preservatives and the like can be included.
  • dosages can be varied depending upon the overall condition of the patient, the nature of the illness being treated and other factors.
  • An example of a suitable oral dosage range is from about 0.1 to about 80 mg/kg per day, in single or divided doses.
  • An example of a suitable parenteral dosage range is from about 0.1 to about 80 mg/kg per day, in single or divided dosages, administered by intravenous or intramuscular injection.
  • An example of a topical dosage range is from about 0.1 mg to about 150 mg, applied externally from about one to four times a day.
  • An example of an inhalation dosage range is from about 0.01 mg/kg to about 1 mg/kg per day.
  • the compounds may be administered in conventional dosages as a single agent or in combination with other therapeutically active compounds.
  • the amide nitrile (7) from above (280mg, 0.93mmol) was dissolved in CH2CI2 and treated with trifluoraceticanhydride (2ml) and trifluoracetic (0.5ml). The reaction was allowed to proceed for 4 hours at which point it was concentrated. The solids that remained were filtered with the aid of CH2CI2 and washed further with CH2CI2 to give the desired product.
  • Step 2 Amide nitrile from Step 2 was dissolved in a mixture of CH2Cl2/trifluoroacetic anhydride/trifluoroacetic acid (58/40/2) and stirred at room temperature overnight. The reaction was then concentrated and the residue taken up into EtOAc. This EtOAc solution was then washed with water, aqueous NaHCO3 (sat) and brine. The organics were dried with MgS04 and concentrated to afford the desired product as a solid that was used without further purification. Step 4
  • the amide was dissolved in CHCl3/ ⁇ t3N (1:1, 30mL) and heated to reflux overnight. The reaction was then concentrated to a yellow gum and the residue taken up into EtOAc and water. The layers were then seperated and the organics washed with brine and dried (MgSO4). The material was used without further purification.
  • Methyl-3-bromo-nicotinate and 3-thiophene boronic acid were dissolved in degassed dioxane (25mL). To the homogeneous solution was added Pd((Ph3)4P)). The reaction was heated to 90oC for 18 hours and then cooled to room temperature and concentrated. The residue was taken up into EtOAc and water. The layers were then separated and the organics washed with brine and dried (MgS ⁇ 4). Flash LC (60% Hexanes/EtOAc) gave the desired product.
  • the amide nitrile (0.064mg, 0.2mmol) was partially dissolved in dichlorethane (5mL). MeS ⁇ 3H (0.039mL, O. ⁇ mmol) was then added and the reaction allowed to proceed overnight at room temperature. The reaction was diluted with CH2CI2 and extracted with aqueous NaHCO3 (sat), water and then dried (MgS04). The desired product was isolated by flash LC (40% EtOAc/ CH2CI2) to give a pale yellow solid. The material was triturated with Et2O, filtered and dried over P2 ⁇ -
  • Step 6 l-F4-Phenyl-2-(5-thiophen-3-yl-pyridin-3-yl)-oxazol-5-yll-pyrrolidin-2-one
  • Chloro amide from above (0.38g, 0.896mmol) was treated with Et3N (5mL) and a small amount of CHCI3 until homogeneous. The reaction was heated to 90f>C for 2hr. The reaction was then cooled to room temperature and concentrated to dryness. The residue was partitioned between EtOAc and aqueous HCl (0.5N). The organics were washed further with water, brine, and dried (MgS ⁇ 4). Flash LC 5%EtOAc/ CH2CI2 gave an off white solid that was triturated with diethylether and dried over P2O5.
  • This compound was prepared in a manner analogous to that described above.
  • VEGF receptor kinase activity is measured by incorporation of radio-labeled phosphate into polyglutamic acid, tyrosine, 4:1 (pEY) substrate.
  • the phosphorylated pEY product is trapped onto a filter membrane and the incorporation of radio- labeled phosphate quantified by scintillation counting.
  • the intracellular tyrosine kinase domains of human KDR (Terman, B.I. et al. Oncogene (1991) vol. 6, pp. 1677-1683.) and Flt-1 (Shibuya, M. et al. Oncogene (1990) vol. 5, pp. 519-524) were cloned as glutathione S-transferase (GST) gene fusion proteins. This was accomplished by cloning the cytoplasmic domain of the KDR kinase as an in frame fusion at the carboxy terminus of the GST gene.
  • GST glutathione S-transferase
  • Soluble recombinant GST-kinase domain fusion proteins were expressed in Spodoptera frugiperda (Sf21) insect cells (Invitrogen) using a baculovirus expression vector (pAcG2T, Pharmingen).
  • Sf21 cells were infected with recombinant virus at a multiplicity of infection of 5 virus particles/ cell and grown at
  • VEGF receptors that mediate mitogenic responses to the growth factor is largely restricted to vascular endothelial cells.
  • HUVECs in culture proliferate in response to VEGF treatment and can be used as an assay system to quantify the effects of KDR kinase inhibitors on VEGF stimulation.
  • quiescent HUVEC monolayers are treated with vehicle or test compound 2 hours prior to addition of VEGF or basic fibroblast growth factor (bFGF).
  • the mitogenic response to VEGF or bFGF is determined by measuring the incorporation of [ 3 H]thymidine into cellular DNA.
  • HUVECs frozen as primary culture isolates are obtained from Clonetics Corp. Cells are maintained in Endothelial Growth Medium (EGM; Clonetics) and are used for mitogenic assays at passages 3-7.
  • EGM Endothelial Growth Medium
  • NUNC #167008 NUNCLON 96-well polystyrene tissue culture plates
  • Assay Medium Dulbecco's modification of Eagle's medium containing 1 g/ml glucose (low-glucose DMEM; Mediatech) plus 10% (v/v) fetal bovine serum (Clonetics).
  • HUVEC monolayers maintained in EGM are harvested by trypsinization and plated at a density of 4PPP cells per 100 ul Assay Medium per well in 96-well plates. Cells are growth- arrested for 24 hours at 37°C in a humidified atmosphere containing 5% C02-
  • Growth- arrest medium is replaced by 100 ul Assay Medium containing either vehicle (0.25% [v/v] DMSO) or the desired final concentration of test compound. All determinations are performed in triplicate. Cells are then incubated at 37 C/5% CO2 for 2 hours to allow test compounds to enter cells.
  • [ 3 H]Thymidine (10 ul/well) is added. q 5. Three days after addition of [ HJthymidine, medium is removed by aspiration, and cells are washed twice with Cell Wash Medium (400 ul well followed by 200 ul well). The washed, adherent cells are then solubilized by addition of Cell Lysis Solution
  • the compounds of formula I are inhibitors of VEGF and thus are useful for the inhibition of neoangiogenesis, such as in the treatment of occular disease, e.g., diabetic retinopathy and in the treatment of cancers, e.g., solid tumors.
  • the instant compounds inhibit VEGF- stimulated mitogenesis of human vascular endothelial cells in culture with IC50 values between 0.01 - 5.0 ⁇ M.
  • These compounds also show selectivity over related tyrosine kinases (e.g. FGFRl and the Src family).

Abstract

L'invention concerne des composés inhibant l'enzyme tyrosine kinase, des compositions contenant ces composés inhibant la tyrosine kinase, ainsi que des procédés d'utilisation de ces inhibiteurs pour traiter des maladies et états associés à la tyrosine kinase, tels que l'angiogenèse, le cancer, l'athérosclérose, la rétinopathie diabétique ou les maladies auto-immunes, chez des mammifères.
PCT/US1999/015200 1998-07-10 1999-07-06 Nouveaux inhibiteurs de l'angiogenese WO2000002871A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002336848A CA2336848A1 (fr) 1998-07-10 1999-07-06 Nouveaux inhibiteurs de l'angiogenese
EP99937204A EP1097147A4 (fr) 1998-07-10 1999-07-06 Nouveaux inhibiteurs de l'angiogenese
AU52082/99A AU747427B2 (en) 1998-07-10 1999-07-06 Novel angiogenesis inhibitors
JP2000559102A JP2002520324A (ja) 1998-07-10 1999-07-06 新規な血管形成インヒビター

Applications Claiming Priority (4)

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US9228598P 1998-07-10 1998-07-10
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AU5208299A (en) 2000-02-01
AU747427B2 (en) 2002-05-16

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